上皮间质转化在肝纤维化中的作用及相关信号通路研究进展

上皮间质转化是指有极性的上皮细胞失去其上皮特征并逐渐转化为具有迁徙和侵袭能力的间充质细胞的过程,其中2型上皮间质转化与肝纤维化密切相关,故近年来上皮间质转化成为肝纤维化及其靶向药物研究的热点。综述上皮间质转化在肝纤维化中的作用及相关信号通路的研究进展,以期为肝纤维化及其靶向药物的研究提供参考。     

MicroRNA Biogenesis Pathway Gene Polymorphisms Are Associated with Breast Cancer Risk

MicroRNAs (miRNAs) play an important role as epigenetic regulators in cancer initiation and progression. One of the mechanisms of miRNA dysregulation is altered functioning of proteins involved in miRNA processing machinery. It has been suggested that single nucleotide polymorphisms (SNPs) within miRNA gene regions, miRNA target genes, and miRNA machinery genes may affect the miRNAs regulation. We selected 25 SNPs in the key genes of miRNA biosynthesis, including DROSHA/RNASEN, DGCR8, DICER1, XPO5, RAN, PIWIL1/HIWI, AGO1/EIF2C1, AGO2, GEMIN4, GEMIN3/DDX20, and DDX5, and investigated the association between these SNPs and the risk of breast cancer. The total number of breast cancer cases and cancer-free controls enrolled in the investigation were 778 (417 breast cancer patients and 361 healthy women). We found that rs11060845 and rs10773771 in the PIWIL1 gene, rs3809142/RAN, rs10719/DROSHA, rs1640299/DGCR8, rs563002/DDX20, rs595055/AGO1, and rs2740348/GEMIN4 were associated with breast cancer risk in Russians.     

胰岛素信号通路相关因子在2型糖尿病合并骨质疏松大鼠肝组织的表达

通过高糖高脂饲料联合小剂量链脲佐菌素和去卵巢手术制备2型糖尿病合并骨质疏松大鼠模型,探讨2型糖尿病合并骨质疏松大鼠肝组织胰岛素信号通路相关因子的表达及意义。结果表明:随着时间延长,2型糖尿病合并骨质疏松组(DOVX组)肝组织IGF-1、IRS-1较其他组mRNA及蛋白表达减少,单纯去卵巢组(NOVX组)IGF-1、IRS-1 mRNA及蛋白表达较假手术对照组(NS组)降低;糖尿病组(DS组)IRS-2较NS组mRNA及蛋白表达下降,但NOVX组与NS组IRS-2 mRNA及蛋白表达比较无明显差别。以上结果表明,2型糖尿病合并骨质疏松的发生可能与肝脏胰岛素信号通路受抑制有关。     

Notch 通路在大鼠肝纤维化发生发展中作用的初探

目的:研究Notch通路在肝纤维发生发展中作用及可能的分子机制。方法:Wistar大鼠40只随机分为正常对照组与病理模型组,病理模型组皮下注射四氯化碳制备肝纤维化模型。8周后将大鼠处死,取肝组织行病理HE染色评价肝纤维化程度并采用免疫组织化学法检测Notch-1蛋白、E-cadherin蛋白与TGF-β1蛋白的表达。结果:肝组织病理HE染色示肝纤维化大鼠肝脏肝细胞坏死、再生明显,胶原纤维沉积明显增加,肝实质结构紊乱。与正常对照组相比,病理模型组notch-1与TGF-β1蛋白表达明显增加,而E-cadherin蛋白的表达明显下降(P<0.01)。结论:Notch通路在大鼠肝纤维化发生发展中可能起重要作用。     

Association of Single Nucleotide Polymorphisms in Wnt Signaling Pathway Genes with Breast Cancer in Saudi Patients

Breast cancer is a complex heterogeneous disease involving genetic and epigenetic alterations in genes encoding proteins that are components of various signaling pathways. Candidate gene approach have identified association of genetic variants in the Wnt signaling pathway genes and increased susceptibility to several diseases including breast cancer. Due to the rarity of somatic mutations in key genes of Wnt pathway, we investigated the association of genetic variants in these genes with predisposition to breast cancers. We performed a case-control study to identify risk variants by examining 15 SNPs located in 8 genes associated with Wnt signaling. Genotypic analysis of individual locus showed statistically significant association of five SNPs located in β-catenin, AXIN2, DKK3, SFRP3 and TCF7L2 with breast cancers. Increased risk was observed only with the SNP in β-catenin while the other four SNPs conferred protection against breast cancers. Majority of these associations persisted after stratification of the cases based on estrogen receptor status and age of on-set of breast cancer. The rs7775 SNP in exon 6 of SFRP3 gene that codes for either arginine or glycine exhibited very strong association with breast cancer, even after Bonferroni''s correction. Apart from these five variants, rs3923086 in AXIN2 and rs3763511 in DKK4 that did not show any association in the overall population were significantly associated with early on-set and estrogen receptor negative breast cancers, respectively. This is the first study to utilize pathway based approach to identify association of risk variants in the Wnt signaling pathway genes with breast cancers. Confirmation of our findings in larger populations of different ethnicities would provide evidence for the role of Wnt pathway as well as screening markers for early detection of breast carcinomas.     

Nrf2 信号通路及其在肝组织中的作用

肝脏是一个多方面高度调节的防御性器官,能够抵御多种化学/ 氧化应激,而在这个防御系统的最前线是一群被称作转录因子的特殊蛋白,这些蛋白能识别并结合于特异性基因启动子区域中特异的DNA 元件,从而调节多种细胞保护性基因的基础型和诱导型表达,发挥细胞保护作用。而转录因子NF-E2 相关因子2（Nrf2）是细胞防御化学/ 氧化应激的重要调节因子之一。综述Nrf2 信号通路中主要调控因子的相互作用、Nrf2 的激活与失活机制以及Nrf2 信号通路在肝组织中的作用。     

Wnt 信号通路GS 蛋白在胃癌中的表达和临床意义

目的:研究Wnt信号通路的中GS蛋白(谷氨酰胺合成酶)在胃癌组织中的表达,探索其在胃癌发生、发展中的意义。方法:用免疫组织化学法测定胃癌组织(110例)、肠化生组织(30例)、不典型增生组织(20例)及慢性浅表性胃炎组织(60例)中GS蛋白表达。用快速尿素酶法与病理组织切片染色法检测上述各组织中HP感染的情况,并予统计学分析比较其差异。结果:胃癌组织GS高蛋白表达与组织分型、分化程度、淋巴结转移密切相关(P<0.05),与肿瘤大小、部位、TNM分期、Borrmann分型、性别、年龄等无明显相关(P>0.05)。GS表达与HP感染密切相关。结论:GS蛋白高表达同胃癌生物学行为密切相关,在胃癌的发生、发展中起重要作用。     

肺纤维化中TGF-β信号传导通路及其靶点治疗

转化生长因子β(TGF-β)是最重要的致肺纤维化细胞因子.TGF-β通过下游的信号转导因子激活成纤维细胞等效应细胞.对TGF信号传导通路各靶点进行干预可能为治疗纤维化疾病提供一种新手段.     

M2 Macrophages Activate WNT Signaling Pathway in Epithelial Cells: Relevance in Ulcerative Colitis

Macrophages, which exhibit great plasticity, are important components of the inflamed tissue and constitute an essential element of regenerative responses. Epithelial Wnt signalling is involved in mechanisms of proliferation and differentiation and expression of Wnt ligands by macrophages has been reported. We aim to determine whether the macrophage phenotype determines the expression of Wnt ligands, the influence of the macrophage phenotype in epithelial activation of Wnt signalling and the relevance of this pathway in ulcerative colitis. Human monocyte-derived macrophages and U937-derived macrophages were polarized towards M1 or M2 phenotypes and the expression of Wnt1 and Wnt3a was analyzed by qPCR. The effects of macrophages and the role of Wnt1 were analyzed on the expression of β-catenin, Tcf-4, c-Myc and markers of cell differentiation in a co-culture system with Caco-2 cells. Immunohistochemical staining of CD68, CD206, CD86, Wnt1, β-catenin and c-Myc were evaluated in the damaged and non-damaged mucosa of patients with UC. We also determined the mRNA expression of Lgr5 and c-Myc by qPCR and protein levels of β-catenin by western blot. Results show that M2, and no M1, activated the Wnt signaling pathway in co-culture epithelial cells through Wnt1 which impaired enterocyte differentiation. A significant increase in the number of CD206+ macrophages was observed in the damaged mucosa of chronic vs newly diagnosed patients. CD206 immunostaining co-localized with Wnt1 in the mucosa and these cells were associated with activation of canonical Wnt signalling pathway in epithelial cells and diminution of alkaline phosphatase activity. Our results show that M2 macrophages, and not M1, activate Wnt signalling pathways and decrease enterocyte differentiation in co-cultured epithelial cells. In the mucosa of UC patients, M2 macrophages increase with chronicity and are associated with activation of epithelial Wnt signalling and diminution in enterocyte differentiation.     

Wnt基因/Wnt信号通路与乳腺癌

Wnt蛋白是一组调控胚胎形成期间细胞间信号传导的高度保守的分泌信号分子.在过去的几年里,由Wnt蛋白触发的不同信号通路已经得到了详尽的研究.Wnt基因与Wnt信号通路组成分子的突变可引起发育缺陷,异常的Wnt信号传导可导致人类疾病包括肿瘤的发生.许多证据都表明,Wnt信号通路的失调与乳腺癌的发生发展密切相关.micro...     

Regulation of SMAD Signaling Pathway by miRNAs Associated with Myocardial Fibrosis: In silico Analysis of Target Gene Networks

Biochemistry (Moscow) - Hypertrophic cardiomyopathy (HCM) is a hereditary heart disease caused by mutations in the sarcomere genes, which is accompanied by myocardial fibrosis leading to...     

IFNL4 and IFNL3 Associated Polymorphisms Strongly Influence the Spontaneous IFN-Alpha Receptor-1 Expression in HCV-Infected Patients

Single-nucleotide polymorphism in IFNL3 gene (rs12979860) predicts spontaneous and therapy-induced HCV clearance. In a previous study from our group PBMC from patients with favourable rs12979860 genotype showed higher levels of IFNAR-1 mRNA. Recently, a dinucleotide polymorphism, ss469415590 (TT or ΔG), has been discovered in the region upstream IFNL3 gene, which is in high linkage disequilibrium with rs12979860. ss469415590[ΔG] is a frameshift variant that creates a novel gene, designed IFNL4, encoding the interferon-lambda 4 protein (IFNL4). The aim of the present study was to extend the analysis of IFNAR-1 mRNA levels to the ss469415590 variants. Our results highlight that the difference of IFNAR-1 mRNA levels between favourable and unfavourable genotype combinations, at both rs12979860 and ss469415590 loci, is stronger than that observed for single polymorphisms at each locus. These findings suggest may represent the biological basis for the observed association between IFNL3 CC and IFNL4 TT/TT genotypes and favourable outcome of either natural HCV infection (clearance vs chronic evolution) or IFN-based therapy.     

The WNT Signaling Pathway Contributes to Dectin-1-Dependent Inhibition of Toll-Like Receptor-Induced Inflammatory Signature

Macrophages regulate cell fate decisions during microbial challenges by carefully titrating signaling events activated by innate receptors such as dectin-1 or Toll-like receptors (TLRs). Here, we demonstrate that dectin-1 activation robustly dampens TLR-induced proinflammatory signature in macrophages. Dectin-1 induced the stabilization of β-catenin via spleen tyrosine kinase (Syk)-reactive oxygen species (ROS) signals, contributing to the expression of WNT5A. Subsequently, WNT5A-responsive protein inhibitors of activated STAT (PIAS-1) and suppressor of cytokine signaling 1 (SOCS-1) mediate the downregulation of IRAK-1, IRAK-4, and MyD88, resulting in decreased expression of interleukin 12 (IL-12), IL-1β, and tumor necrosis factor alpha (TNF-α). In vivo activation of dectin-1 with pathogenic fungi or ligand resulted in an increased bacterial burden of Mycobacteria, Klebsiella, Staphylococcus, or Escherichia, with a concomitant decrease in TLR-triggered proinflammatory cytokines. All together, our study establishes a new role for dectin-1-responsive inhibitory mechanisms employed by virulent fungi to limit the proinflammatory environment of the host.     

Wnt信号通路GS蛋白在胃癌中的表达和临床意义

目的：研究wnt信号通路的中GS蛋白（谷氨酰胺合成酶）在胃癌组织中的表达,探索其在胃癌发生、发展中的意义。方法：用免疫组织化学法测定胃癌组织（110例）、肠化生组织（30例）、不典型增生组织（20例）及慢性浅表性胃炎组织（60例）中GS蛋白表达。用快速尿素酶法与病理组织切片染色法检测上述各组织中HP感染的情况,并予统计学分析比较其差异。结果：胃癌组织GS高蛋白表达与组织分型、分化程度、淋巴结转移密切相关（P〈0．05）,与肿瘤大小、部位、TNM分期、Borrmann分型、性别、年龄等无明显相关（P〉0．05）。GS表达与HP感染密切相关。结论：GS蛋白高表达同胃癌生物学行为密切相关,在胃癌的发生、发展中起重要作用。     

综述:mTOR信号通路与“炎-癌”转变

慢性炎症是指刺激因素持续作用或其他原因导致的难以消退的炎症反应．它与许多重大疾病的发生、发展密切相关．近年来,慢性炎症在癌症发生发展中的关键作用得到普遍认可,其促癌作用的机制已成为当前生命科学研究热点之一．哺乳动物雷帕霉素靶蛋白(mammalian target of rapamycin, mTOR)是接受细胞内外各种信号、调节细胞生长与代谢的关键分子,多数肿瘤存在mTOR通路的过度激活．最近,我们与其他实验室的研究发现mTOR通路在“炎-癌”转变中起重要作用．本综述将对慢性炎症与癌症的关系、慢性炎症的促癌作用机制做一概括介绍,重点讨论mTOR信号通路介导慢性炎症促癌效应的作用、机制及未来研究方向,为慢性炎症恶性转化分子机制研究提供新的观点．     

Melanocortin-4 Receptor Gene Polymorphisms in Obese Patients

Obesity is a complex disease caused by both genetics and environmental factors. Melanocortin-4 receptor (MC4R) (MIM 155541) gene polymorphisms were reported to be the cause of monogenic obesity in humans. We studied three polymorphisms (Val50Met, Val103Ile, and Ser58Cys) and a mutation (Asn274Ser) of the MC4R gene in 203 obese patients and in 110 healthy subjects in the Turkish population. A high incidence of Val103Ile and Val50Met polymorphisms as well as the Asn274Ser mutation was found in the obese patients, whereas no significant correlation was found regarding the Ser58Cys polymorphism. We conclude that there is a concordance between the polymorphisms (Val103Ile, Val50Met, Ser58Cys) that were first studied in the Turkish population with obesity.     

The Novel Secreted Adipokine WNT1-inducible Signaling Pathway Protein 2 (WISP2) Is a Mesenchymal Cell Activator of Canonical WNT

WNT1-inducible-signaling pathway protein 2 (WISP2) is primarily expressed in mesenchymal stem cells, fibroblasts, and adipogenic precursor cells. It is both a secreted and cytosolic protein, the latter regulating precursor cell adipogenic commitment and PPARγ induction by BMP4. To examine the effect of the secreted protein, we expressed a full-length and a truncated, non-secreted WISP2 in NIH3T3 fibroblasts. Secreted, but not truncated WISP2 activated the canonical WNT pathway with increased β-catenin levels, its nuclear targeting phosphorylation, and LRP5/6 phosphorylation. It also inhibited Pparg activation and the effect of secreted WISP2 was reversed by the WNT antagonist DICKKOPF-1. Differentiated 3T3-L1 adipose cells were also target cells where extracellular WISP2 activated the canonical WNT pathway, inhibited Pparg and associated adipose genes and, similar to WNT3a, promoted partial dedifferentiation of the cells and the induction of a myofibroblast phenotype with activation of markers of fibrosis. Thus, WISP2 exerts dual actions in mesenchymal precursor cells; secreted WISP2 activates canonical WNT and maintains the cells in an undifferentiated state, whereas cytosolic WISP2 regulates adipogenic commitment.